Effects of Genetic Polymorphisms of CYP2B6 on the Pharmacokinetics of Bupropion and Hydroxybupropion in Healthy Chinese Subjects

Background Bupropion (BUP) is an antidepressant and its pharmacological activity is mediated by its major metabolite, hydroxybupropion (HBUP). We investigated the effects of genetic polymorphisms of CYP2B6 on BUP and HBUP to provide certain evidence on the clinical rational administration of BUP. Material/Methods Plasma BUP and HBUP concentrations were assayed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results A total of 23 healthy volunteers (eleven participants with CYP2B6*1/*1, 7 participants with CYP2B6*1/*6, 3 participants with CYP2B6*4/*6, and 2 participants with CYP2B6*1/*4) received orally administered 150 mg of BUP according to protocol. Blood samples were obtained up to 96 hours after administration. The whole blood was subject to genotyping by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The concentration-time curve (AUC(0®96)), maximum plasma concentration (Cmax), and terminal half-life (t1/2) values of BUP in CYP2B6*1/*4 were lower than those of CYP2B6*1/*1. By contrast, the time to Cmax (tmax) value of the former was higher than that of the latter. The HBUP AUC(0®96) values in CYP2B6*4/*6 and CYP2B6*1/*4 increased to values 1.12-fold and 1.98-fold, compared with CYP2B6*1/*1 carriers. However, the HBUP AUC(0®96) value in CYP2B6*1/*1 was 1.51-fold higher than that in CYP2B6*1/*6. Similarly, the HBUP Cmax values in CYP2B6*4/*6 and CYP2B6*1/*4 increased by 1.12-fold and 1.97-fold, whereas the HBUP Cmax value in CYP2B6*1/*6 decreased to a value 1.64-fold lower than that in CYP2B6*1/*1. Conclusions Genetic polymorphisms of CYP2B6 influence the pharmacokinetic parameters of BUP and HBUP and thus establish rational BUP administration for Chinese patients in clinical settings.

[1]  Mohamed E A Abdelrahim,et al.  CYP2B6rs2279343 Is Associated with Improved Survival of Pediatric Rhabdomyosarcoma Treated with Cyclophosphamide , 2016, PloS one.

[2]  E. Kharasch,et al.  Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism , 2015, Anesthesiology.

[3]  E. Şahin.  Evaluation of antiviral resistant hepatitis B virus subpopulations in patients with chronic hepatitis B by using terminal restriction fragment length polymorphism , 2015, VirusDisease.

[4]  E. Molden,et al.  Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data , 2015, Therapeutic drug monitoring.

[5]  J. Krieger,et al.  CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy , 2015, European Journal of Clinical Pharmacology.

[6]  Abdul Rasheed Mohammed,et al.  Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction. , 2015, Chemico-biological interactions.

[7]  É. Carniel,et al.  Typing and Clustering of Yersinia pseudotuberculosis Isolates by Restriction Fragment Length Polymorphism Analysis Using Insertion Sequences , 2014, Journal of Clinical Microbiology.

[8]  Ulrich M. Zanger,et al.  Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance , 2013, Front. Genet..

[9]  N. Benowitz,et al.  Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state , 2013, Pharmacogenetics and genomics.

[10]  Nicole L. Nollen,et al.  CYP2B6 and Bupropion's Smoking‐Cessation Pharmacology: The Role of Hydroxybupropion , 2012, Clinical pharmacology and therapeutics.

[11]  P. Hollenberg,et al.  Inhibition of Bupropion Metabolism by Selegiline: Mechanism-Based Inactivation of Human CYP2B6 and Characterization of Glutathione and Peptide Adducts , 2012, Drug Metabolism and Disposition.

[12]  Wei Zhang,et al.  Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men. , 2012, British Journal of Clinical Pharmacology.

[13]  Z. Desta,et al.  Effects of the CYP2B6*6 Allele on Catalytic Properties and Inhibition of CYP2B6 In Vitro: Implication for the Mechanism of Reduced Efavirenz Metabolism and Other CYP2B6 Substrates In Vivo , 2012, Drug Metabolism and Disposition.

[14]  P. Shrivastav,et al.  Sensitive, selective and rapid determination of bupropion and its major active metabolite, hydroxybupropion, in human plasma by LC-MS/MS: application to a bioequivalence study in healthy Indian subjects. , 2011, Biomedical chromatography : BMC.

[15]  C. Charlier,et al.  Ultra-performance liquid chromatography- tandem mass spectrometry method for the determination of bupropion and its main metabolites in human whole blood. , 2010, Journal of analytical toxicology.

[16]  T. Shioda,et al.  Effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine levels when co-administered with rifampicin in HIV/TB co-infected Thai adults , 2010, AIDS research and therapy.

[17]  T. Monif,et al.  Bioequivalence Studies of Tacrolimus Capsule under Fasting and Fed Conditions in Healthy Male and Female Subjects , 2008, Arzneimittel-Forschung (Drug Research).

[18]  E. Kharasch,et al.  Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[19]  M. Schwab,et al.  Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. , 2007, Pharmacogenomics.

[20]  B. Birmaher,et al.  Steady-state clinical pharmacokinetics of bupropion extended-release in youths. , 2006, Journal of the American Academy of Child and Adolescent Psychiatry.

[21]  J. Jefferson,et al.  Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. , 2005, Clinical therapeutics.

[22]  A. S. Gross,et al.  HPLC assay for bupropion and its major metabolites in human plasma. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[23]  K. Midha,et al.  Exposure measures applied to the bioequivalence of two sustained release formulations of bupropion. , 2005, International journal of clinical pharmacology and therapeutics.

[24]  P. Svastova,et al.  IS900 Restriction Fragment Length Polymorphism (RFLP) Analysis of Mycobacterium avium subsp. paratuberculosis Isolates from Goats and Cattle in Norway , 2005, Acta veterinaria Scandinavica.

[25]  J. Henion,et al.  High-throughput liquid chromatography-tandem mass spectrometry determination of bupropion and its metabolites in human, mouse and rat plasma using a monolithic column. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[26]  S. Rijpkema,et al.  Identification of cagA Tyrosine Phosphorylation DNA Motifs in Helicobacter pylori Isolates from Peptic Ulcer Patients by Novel PCR-Restriction Fragment Length Polymorphism and Real-Time Fluorescence PCR Assays , 2003, Journal of Clinical Microbiology.

[27]  H. Jinno,et al.  Functional characterization of cytochrome P450 2B6 allelic variants. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[28]  F. Gozzo,et al.  Mass spectrometric quantitation of chiral drugs by the kinetic method. , 2001, Analytical chemistry.

[29]  C. Lindley,et al.  Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[30]  D. Greenblatt,et al.  CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[31]  H. Cohen,et al.  A Brief Depression Scale for Use in the Medically Ill , 1992, International journal of psychiatry in medicine.

[32]  H. Cohen,et al.  Survival and Health Care Utilization in Elderly Medical Inpatients With Major Depression , 1989, Journal of the American Geriatrics Society.

[33]  Stephen R. Rapp,et al.  Detecting depression in elderly medical inpatients. , 1988, Journal of consulting and clinical psychology.

[34]  M. Hiratsuka,et al.  Two novel single nucleotide polymorphisms (SNPs) of the CYP2D6 gene in Japanese individuals. , 2005, Drug metabolism and pharmacokinetics.

[35]  J. Posner,et al.  The disposition of bupropion and its metabolites in healthy male volunteers after single and multiple doses , 2004, European Journal of Clinical Pharmacology.